Pharmaceutical products providing enhanced analgesia

ABSTRACT

An analgesic composition comprising capsaicin or a capsaicin analogue and an analgesic selected from the class of non-steroidal anti-inflammatory, antipyretic and analgesic drugs is disclosed. This combination has been found to exhibit unexpectedly enhanced analgesic activity in humans and lower animals without a corresponding increase in undesirable side effects.

This is a division of application Ser. No. 684,642, filed on Dec. 24,1984, now U.S. Pat. No. 4,681,897.

TECHNICAL FIELD

The present invention relates to analgesic compositions comprisingcapsaicin or a capsaicin analog combined with a drug selected from theclass of non-steroidal anti-imflammatory, antipyretic and analgesiccompounds. These compositions, when administered to humans or loweranimals, provide a synergistic analgesic effect while minimizingundesirable side effects and toxicity.

Capsaicin and its derivatives appear to produce an analgesic effectthrough a mechanism largely unrelated to that of the other twocategories of analgesics, opioids (narcotics) and non-steroidalanalgesics (aspirin-like drugs). Since both capsaicin and thenon-steroidals produce an analgesic effect, although apparently throughdifferent mechanisms, it might be expected that their combined effectwould be at best additive. However, tests have shown that the analgesiceffect of the combination is not merely the sum of the effects of eachcomponent, but rather an unexpected, greatly enhanced synergisticeffect. Furthermore, the undesirable side effects of the two categoriesof analgesics are not closely related and the addition of the secondanalgesic does not appear to potentiate the side effects of the first.It is therefore possible to combine the two analgesics in such a dosageas to provide greatly enhanced analgesia with no enhancement of sideeffects. Depending on the dosages employed, the capsaicin may eitherpotentiate the degree of analgesia beyond that obtainable using thenon-steroidal alone, or it may induce analgesia at dosages where noanalgesic effect is obtained from either component alone.

BACKGROUND OF THE INVENTION

Traditionally, analgesics have fallen into two broad categories. Simple,non-narcotic analgesics, such as aspirin, which appear to work byinhibition of prostaglandin synthetase, are effective against pain ofintegumental origin such as headache and muscle aches, but are oftenineffective in controlling deeper, more intense pain. Furthermore, theymay cause undesirable side effects even at therapeutic dosages. The mostcommon of these side effects is a propensity to induce dyspepsia andgastrointestinal bleeding. At higher dosages, the salicylates may havetoxic effects on the central nervous system consisting of stimulation(including convulsions) followed by depression. Headache, dizziness,mental confusion, hearing difficulties and hyperventilation may alsooccur. Gastrointestinal symptoms may include epigastric distress, nauseaand vomiting. The narcotic analgesics appear to work through interactionwith the endorphin/enkephalin receptor system of the central nervoussystem and are useful in controlling pain which is too intense to becontrolled by the weaker, non-narcotic analgesics. However,centrally-acting narcotic analgesics have several serious undesirableside effects, including the development of physical dependence andtolerance, sedation, respiratory depression, hypotension, increase incerebrospinal fluid pressure, nausea, vomiting and constipation. In somepatients, particularly the chronically ill, the narcotic side effectsmake it impossible to administer dosages sufficient to adequatelycontrol pain over the required time period.

This invention combines capsaicin or a capsaicin analog with a drug fromthe class of non-narcotic, non-steroidal anti-inflammatory, antipyreticand analgesic compounds (often referred to as "aspirin-like" drug, sincethe prototypical compound is aspirin), producing a synergistic incresein analgesia without a corresponding increase in side effects. Thedegree of analgesia produced by this combination has been found in somecases to be equivalent to that formerly obtainable only through the useof narcotics. Thus, the claimed combination makes it possible to controlpain which is too severe to be adequately controlled by thenon-steroidals alone, while avoiding the serious side effects andaddiction potential inherent in the use of opioids.

It has been recently discovered that capsaicin, a natural product ofcertain species of the genus Capsicium, induces analgesia. Capsaicin(8-methyl-N-vanillyl-6Z-nonenamide) and "synthetic" capsaicin(N-vanillyl-nonanamide) are disclosed as analgesics in U.S. Pat. No.4,313,958, LaHann, issued Feb. 2, 1982. Analgesic activity of capsaicinhas also been discussed in the chemical and medical literature,including Yaksh, et al, Science, 206, pp 481-483 (1979); Jancso, et al,Naunyn-Schmiedeberg's Arch. Pharmacol., Vol. 311, pp 285-288 and Holzeret al, Eur. J. Pharm. Vol. 58, pp 511-514 (1979). U.S. Pat. No.4,238,505, Nelson, issued Dec. 9, 1980, discloses 3-hydroxyacetanilidefor use in producing analgesia in animals. European Patent ApplicationNo. 0089710, LaHann, et al, published Sept. 28, 1983, describeshydroxyphenylacetamides with analgesic and anti-irritant activity.Similarly, analgesic and anti-irritant activity is disclosed forN-vanillylsulfonamides in U.S. Pat. No. 4,401,663, Buckwalter, et al,issued Aug. 30, 1983; N-vanillylureas in European Patent Application No.0068590, Buckwalter, et al, published Jan. 5, 1983; N-vanillylcarbamatesin European Patent Application No. 0068592, Buckwalter, et al, publishedJan. 5, 1983; N-[(substituted phenyl)methyl]alkynlamides in U.S. patentapplication Ser. No. 514,204, Janusz, et al, filed July 14, 1983;methylene substituted N-[(substituted phenyl)methyl]-alkanamides in U.S.patent application Ser. No. 514,205, Janusz, et al, filed July 14, 1983;N[(substituted phenyl)methyl]-cis-monounsaturated alkenamides in U.S.patent application Ser. No. 514,206, LaHann, et al, filed July 14, 1983;and N-[substituted phenyl)methyl]-diunsaturated amides in U.S. patentapplication Ser. No. 514,207, LaHann, et al, filed July 14, 1983.However, none of these references suggest in any way the desirability ofconcurrent administration of capsaicin or a capsaicin derivative with anon-steroidal. Further, the art suggests that it is extremely difficultto predict when a synergistic effect will be obtained from theconcurrent administration of two pharmaceutical compounds which takeeffect through different mechanisms.

Although there are many patents which disclose analgesic andanti-inflammatory compositions containing a combination of two or moremechanistically unrelated analgesic and/or anti-inflammatory compounds,none of these compounds has a structure at all similar to that ofcapsaicin. See U.S. Pat. No. 4,404,210, Schmidt, issued Sept. 13, 1983;U.S. Pat. No. 4,083,981, Yamamoto, issued Apr. 11, 1978; U.S. Pat. No.4,315,936, Capetola et al, issued Feb. 16, 1982; U.S. Pat. No.4,379,789, Capetola et al, issued Apr. 12, 1983; and U.S. Pat. No.4,275,059, Flora, et al, issued June 23, 1981.

Thus, based on the art, one could not have predicted that thecombination of capsaicin or a capsaicin analog with a non-steroidalwould result in a synergistic increase in analgesia.

SUMMARY OF THE INVENTION

It has now been found that combinations of capsaicin derivatives of thegeneral formula ##STR1## wherein R₁ is OH or OCH₃, R₂ is OH or ashort-chain ester, X is ##STR2## and R is a C₅ -C₁₁ alkyl, C₅ -C₁₁alkenyl, C₁₁ -C₂₃ cis alkenyl, C₁₁ -C₂₃ alkynyl, C₁₁ -C₂₃ alkadienyl, orC₁₁ -C₂₃ methylene substituted alkane, with a non-steroidal analgesic atweight ratios of capsaicinoid to non-steroidal from about 20:1 to 1:20,and preferably from about 10:1 to 1:10, provide unexpectedly enhancedanalgesic activity in humans and lower animals without a correspondingincrease in undesirable side effects.

Another aspect of the present invention comprises the method ofalleviating pain in humans and lower animals by concurrentadministration of a safe and effective amount of the analgesiccomposition described above.

DETAILED DESCRIPTION OF THE INVENTION Definitions

By the term "comprising" as used herein is meant that various otherinert ingredients, compatible drugs and medicaments, and steps can beemployed in the compositions and methods of the present invention aslong as the critical capsaicinoid/non-steroidal combination is presentin the compositions and is used in the manner disclosed. The term"comprising" thus encompasses and includes the more restrictive terms"consisting essentially of" and "consisting of" which characterize theuse of the compositions and methods disclosed herein.

By "compatible" herein is meant that the components of the compositionare capable of being commingled without interacting in a manner whichwould substantially decrease the analgesic efficacy of the totalcomposition under ordinary use situations.

By "administer concurrently" is meant either the administration of asingle composition containing both the capsaicinoid and thenon-steroidal, or the administration of the capsaicinoid and thenon-steroidal as separate compositions within a short enough time periodthat the effective result is equivalent to that obtained when bothcompounds are administered as a single composition. Normally this wouldinvolve two separate dosages given within 10 minutes of each other.However, since many capsaicinoids retain effectiveness over unusuallylong time periods (possibly up to 3 days in the same cases) and mostnon-steroidals provide effective analgesia for relatively short timeperiods (4-8 hours), it may be desirable in some cases to implement atherapeutic regimen whereby each component is administered according toa schedule determined by its own period of analgesic effectiveness inorder to maintain optimum effectiveness of the combination. Thepreferred method of administration is as a single composition.

All percentages and ratios herein are by weight unless otherwisespecified.

Compositions

The compositions of the present invention comprise a safe and effectiveamount of:

(a) capsaicin or a capsaicin analog,

(b) a compound selected from the group of non-steroidalanti-inflammatory, antipyretic and analgesic drugs, and theirpharmaceutically-acceptable salts; and

(c) a pharmaceutically-acceptable carrier.

A safe and effective amount of the composition is that amount whichprovides analgesia, thereby alleviating or preventing the pain beingtreated at a reasonable benefit/risk ratio, as is intended with anymedical treatment. Obviously, the amount of the composition used willvary with such factors as the particular condition that is beingtreated, the severity of the condition, the duration of the treatment,the physical condition of the patient, the nature of concurrent therapy(if any), the method of administration, and the specific formulation andcarrier employed.

By the term "capsaicin or a capsaicin analog" or "capsaicinoid" is meanta compound of the general formula ##STR3## wherein R₁ is selected fromthe group consisting of OH and OCH₃, R₂ is selected from the groupconsisting of ##STR4## R₃ is selected from the group consisting of a C₁-C₄ alkyl, phenyl, and methyl, X is selected from the group consistingof ##STR5## and R is selected from the group consisting of a C₅ -C₁₁alkyl, C₅ -C₁₁ alkenyl, C₁₁ -C₂₃ cis alkenyl, C₁₁ -C₂₃ alkynyl, C₁₁ -C₂₃alkadienyl and C₁₁ -C₂₃ methylene substituted alkane.

Preferred compounds include those wherein both R₁ and R₂ are OH and X is##STR6## and those wherein R₁ is OCH₃, R₂ is OH or R₃ CO and X is##STR7##

Preferred R groups include C₇ -C₁₀ alkyls and trans alkenyls, and C₁₆-C₂₁ cis alkenyls and alkadienyls. The preferred moieties within thesegroups include C₈ H₁₇, C₉ H₁₇ and C₁₇ H₃₃. Preferred capsaicin analogsinclude N-vanillyl-alkadienamides, N-vanillyl-alkanedienyls, andN-vanillyl-cis-monounsaturated alkenamides. A particularly preferredcapsaicinoid is N-vanillyl-9Z-octadecenamide (N-vanillyloleamide).

Preferred capsaicin analogs and methods for their preparation aredescribed in the following Patents and Patent Applications, allincorporated by reference herein: Capsaicin(8-methyl-N-vanillyl-6E-nonenamide) and "synthetic" capsaicin(n-vanillylnonanamide) are disclosed as analgesics in U.S. Pat. No.4,313,958, LaHann, issued Feb. 2, 1982. European Patent Application No.0089710, LaHann, et al, published Sept. 28, 1983, describeshydroxyphenylacetamides with analgesic and anti-irritant activity.Similary, analgesic and anti-irritant activity is disclosed forN-vanillylsulfonamides in European Patent Application No. 0068591,Buckwalter, et al, published Jan. 5, 1983; N-vanillylureas in EuropeanPatent Application No. 0068590, Buckwalter, et al, published Jan. 5,1983; N-vanillylcarbamates in European Patent Application No. 0068592,Buckwalter, et al, published Jan. 5, 1983; N-[(substitutedphenyl)methyl]alkynylamides in U.S. patent application Ser. No. 514,204,Janusz, et al, filed July 14, 1983; methylenesubstituted-N-[(substituted phenyl)methyl]-alkanamides in U.S. patentapplication Ser. No. 514,205, Janusz, et al, filed July 14, 1983;N[(substituted phenyl)methyl]-cis-monounsaturated alkenamides in U.S.patent application Ser. No. 514,206, LaHann, et al, filed July 14, 1983;and N-[(substituted phenyl)methyl]-diunsaturated amides in U.S. patentapplication Ser. No. 514,207, LaHann, et al, filed July 14, 1983.

By "non-steroidal anti-inflammatory, antipyretic and analgesic drugs",or "non-steroidal", is meant a heterogeneous group of compounds, oftenchemically unrelated (although most of them are organic acids) whichshare certain therapeutic actions and side effects. Their therapeuticactivity appears to depend to a large extent upon the inhibition ofprostaglandin biosynthesis. Their primary use is to provide symptomaticrelief from pain and inflammation associated with certain diseases,particularly musculoskeletal disorders such as rheumatoid arthritis andosteoarthritis. These compounds are often referred to as "aspirin-likedrugs", since the prototypical compound is aspirin. The pharmacologicalproperties and therapeutic uses of the compounds included within thisclassification are described in detail in Goodman and Gilman,"Analgesic-Antipyretics and Antiinflammatory Agents; Drugs Employed inthe Treatment of Gout", The Pharmacological Basis of Therapeutics, 6thEd., Ch. 29 (1980); Verbeeck et al, "Clinical Pharmacokinetics ofNon-steroidal Anti-inflammatory Drugs", Clinical Pharmakinetics 8, pp297-331 (1983), and Scherrer and Whitehouse, Antiinflammatory AgentsChemistry & Pharmacology, Vol. 1, Academic Press, New York (1974); allincorporated by reference herein.

Specific classes of non-steroidals useful in the present invention aredisclosed in detail in the following U.S. Patents, all incorporated byreference herein: U.S. Pat. No. 4,275,059, Flora, et al, issued June 23,1983, discloses salicylic acid, its pharmaceutically-acceptable salts,and its pharmaceutically-acceptable esters and derivatives; U.S. Pat.No. 4,264,582, Flora, et al, issued Apr. 28, 1981, disclosesp-(isobutylphenyl) acetic acid compounds, including the parent acid(ibufenac) and its salts and esters, and derivatives thereof; U.S. Pat.No. 4,282,214, Flora, et al, issued Aug. 4, 1981, discloses variousphenylacetic acid derivatives, their pharmaceutically-acceptable salts,and their pharmaceutically-acceptable esters; U.S. Pat. No. 4,216,212,Flora, et al, issued Aug. 5, 1980, discloses pyrazolidine compounds,their pharmaceutically-acceptable salts, and theirpharmaceutically-acceptable esters; U.S. Pat. No. 4,269,828, Flora, etal, issued May 26, 1981, discloses indole compounds, theirpharmaceutically-acceptable salts, and their pharmaceutically-acceptableesters.

Specifically preferred non-steroidals may be roughly divided into fourgeneral classifications. The salicylates include compounds such asacetylsalicylic acid (aspirin), salicylic acid, sodium salicylate,diflunisal, and methyl salicylate. The salicylate-like anti-inflammatoryagents include compounds such as phenylbutazone, indomethacin, zomapiracacid, sulindac, fluproquazone, and mefenamic acid. The arylalkanoicacids include ibuprofen, naproxen, ketoprofen, fenoprofen, suprofen,flurbiprofen, benoxaprofen, pirprofen, and carprofen. Thesalicylate-like analgesic-antipyretics include acetaminophen andphenacetin. In some cases, the non-steroidals may be mixed with eachother or with other drugs such as caffeine. Two popular analgesiccombinations are aspirin, phenacetin and caffeine (APC) and aspirin,phenacetin and acetaminophen. Non-steroidals most preferred for use inthe capsaicinoid-non-steroidal combination include acetylsalicylic acid(aspirin), ibuprofen, acetaminophen, diflunisal, naproxen, fenoprofen,and mefenamic acid. A specifically preferred combination is APC.

Weight ratios of capsaicinoid to non-steroidal useful in the presentinvention range from about 20:1 to about 1:20, with the preferred ratioranging from about 10:1 to about 1:10. The optimum weight ratio isdependent primarily upon the relative strength of the particularcapsaicinoid and non-steroidal used, and the type of severity of thepain being treated. As a representative example, preferred weight ratiosof capsaicinoid:acetylsalicylic acid (aspirin) may range from about 3:1to about 1:3; preferred weight ratios of capsaicinoid:diflunisal mayrange from about 3:1 to about 1:3; preferred weight ratios ofcapsaicinoid:acetaminophen may range from about 3:1 to about 1:3; andpreferred weight ratios of capsaicinoid:ibuprofen may range from about5:1 to about 1:5. The preferred weight ratio for the preferredcombination of N-vanillyl-9Z-octadecenmaide and aspirin is about 2:1.

By "pharmaceutically acceptable salts" is meant those salts of the abovedisclosed acids which are toxicologically safe for topical or oraladministration. These include the sodium, calcium, potassium, magnesium,ammonium, lysine, and arginine salts.

By "pharmaceutically acceptable carrier" is meant a solid or liquidfiller, diluent or encapsultaing substance which may be safely used insystemic or topical administration. Depending upon the particular routeof administration, a variety of pharmaceutically-acceptable carriers,well-known in the art, may be used. These include solid or liquidfillers, diluents, hydrotropes, surface-active agents, and encapsulatingsubstances. The amount of the carrier employed in conjunction with thecapsaicinoid/opioid combination is sufficient to provide a practicalquantity of material per unit dose of analgesic.

Pharmaceutically-acceptable carriers for systemic administration, thatmay be incorporated into the compositions of this invention, includesugars, starches, cellulose and its derivatives, malt, gelatin, talc,calcium sulfate, vegetable oils, synthetic oils, polyols, alginic acid,phosphate buffer solutions, emulsifiers, isotonic saline, andpyrogen-free water. Specific pharmaceutically-acceptable carriers aredescribed in the following U.S. patent applications, all incorporated byreference herein: U.S. Pat. No. 4,401,663, Buckwalter, et al, issuedAug. 30, 1983; European Patent Application No. 089710, LaHann, et al,published Sept. 28, 1983; and European Patent Application No. 0068592,Buckwalter, et al, published Jan. 5, 1983. Preferred carriers forparenteral administration include propylene glycol, ethyl oleate,pyrrolidone, aqueous ethanol, sesame oil, corn oil, and combinationsthereof.

Various oral dosage forms can be used, including such solid forms astablets, capsules, granules and bulk powders. Tablets can be compressed,tablet triturates, enteric-coated, sugar-coated, film-coated or multiplecompressed, containing suitable binders, lubricants, diluents,disintegrating agents, coloring agents, flavoring agents, flow-inducingagents, and melting agents. Liquid oral dosage forms include aqueoussolutions, emulsions, suspensions, solutions and/or suspensionsreconstituted from non-effervescent granules and effervescentpreparations reconstituted from effervescent granules, containingsuitable solvents, preservatives, emulsifying agents, suspending agents,diluents, sweeteners, melting agents, coloring, and flavoring agents.Preferred carriers for oral administration include ethyl oleate, methylcellulose, gelatin, propylene glycol, cottonseed oil, sesame oil, peanutoil, corn oil, soybean oil, oil and water emulsions, andself-emulsifying oils either as free-flowing liquids or encapsulated insoft gelatin capsules. Specific examples of pharmaceutically-acceptablecarriers and excipients that may be used to formulate oral dosage forms,which may be used in formulating oral dosage forms containingmonoalkenamides, are described in U.S. Pat. No. 3,903,297. Robert,issued Sept. 2, 1975, incorporated by reference herein. Techniques andcompositions for making solid oral dosage forms are described inMarshall, "Solid Oral Dosage Forms", Modern Pharmaceutics, Vol. 7,(Banker and Rhodes, editors), 359-427 (1979), incorporated by referenceherein.

Specific systemic and topical formulations useful in this invention aredescribed in the following U.S. patent applications, relating tospecific capsaicin analogs and methods of treatment, which areincorporated by reference herein: U.S. Pat. No. 4,401,663, Buckwalter,et al, issued Aug. 30, 1983; and European Patent Application No.0089710; LaHann, et al, published Sept. 28, 1983; European PatentApplication No. 0068590, Buckwalter, et al, published Jan. 5, 1983; andEuropean Patent Application No. 0068592, Buckwalter, et al, publishedJan. 5, 1983. Topical vehicles, useful herein, are disclosed in thefollowing U.S. patent applications, incorporated by reference herein:"Improved Penetrating Topical Pharmaceutical Compositions Combining1-dodecylazacycloheptan-2-one", Ser. No. 506,275, Cooper, filed June 21,1983; "Penetrating Topical Pharmaceutical Compositions ContainingN-(1-hydroxyethyl)-pyrrolidone", Ser. No. 506,273, Cooper, filed June21, 1983; and "Compounds Useful for Producing Analgesia", Ser. No.514,206, LaHann and Buckwalter, filed July 14, 1983.

Methods for Producing Analgesia

The present invention also encompasses methods for providing analgesiain humans or lower animals by administering concurrently to the human orlower animal in need of such treatment a safe and effective amount of acapsaicinoid/non-steroidal combination or a composition containing thesame. Dosages required, as well as methods of administration, aredependent on the type of nonsteroidal employed, the physical conditionof the patient, the severity of the pain which must be prevented oralleviated, the relative severity and importance of adverse sideeffects, and other factors within the judgment of the physician. Thepreferred method of administration in most cases will be orally.

The maximum dosage of the preferred capsaicin analogue vanillyloleamide(VO) which would normally be administered orally to an average adultwithout unacceptable side effects is about 2000 mg (35.4 mg/kg). Theminimum effective dosage is about 50 mg (0.85 mg/kg). The maximum dosageof a non-steroidal which can be administered to the average adult isalso about 2000 mg (35.4 mg/kg). Thus, the maximum allowable dosage ofthe combination will be about 2000 mg (35.4 mg/kg). It should be notedthat a sub-effective dosage of one compound may effectively potentiatethe other compound; therefore, less-than-minimum dosages of eachcomponent may be utilized in some cases. Thus, when dealing with safeand effective dosage levels of the present invention, it is moreappropriate to speak of safe and effective dosages of the combinationrather than of the individual components.

The compositions and combinations of this invention can be used to treatand prevent pain and inflammation associated with certain diseases,particularly muscularskeletal disorders, and to provide analgesia invarious disorders at the deeper structures, muscles, tendons, bursa andjoints associated with disease and trauma, and in various otherconditions in which capsaicinoids and/or non-steroidals have heretoforebeen used to alleviate pain and discomfort.

The compositions of the instant invention are normally administeredeither topically or orally.

The following non-limiting Examples illustrate the compositions, methodsof treatment, and uses of the present invention.

EXAMPLE I

An analgesic composition for oral administration was made using thefollowing ingredients:

N-Vanillyl-9Z-octadecenamide: 120 mg

Aspirin: 60 mg

Methylcellulose: 30 mg

Saline: 6.0 ml

The composition was prepared by dissolving the methylcellulose in thesaline to yield a 0.5% solution, after which the solid aspirin andN-vanillyl-9-octadecenamide were added and uniformly suspended in thesolution by exposure to sonication. Male mice weighing approximately 25g were orally dosed with a volume of this suspension sufficient todeliver 200 mg/kg of the octadecenamide and 100 mg/kg of the aspirin.Identical groups of mice were dosed orally with similarly preparedformulations which lacked either the aspirin, the octadecenamide, orboth. Analgesic activity was demonstrated using the phenylquinonewrithing test.

EXAMPLE II

An analgesic composition for oral administration was made using thefollowing ingredients:

N-vanillyl-9Z-octadecenamide: 120 mg

Ibuprofen: 30 mg

Methylcellulose: 30 mg

Saline: 6.0 ml

The methylcellulose suspending agent was dissolved in the saline toyield a 0.5% solution, to which the two drugs were added. A homogeneoussuspension was achieved by the aid of sonication. Male mice weighingapproximately 25 g were dosed by gavage with 250 mg/kg of the mixture.Analgesic activity was demonstrated using the phenylquinone writhingtest.

EXAMPLE III

An analgesic composition for oral administration was made using thefollowing ingredients:

N-vanillyl-9Z-octadecenamide: 120 mg

Iburofen: 30 mg

Ethyl oleate: 6.0 ml

The two analgesic agents were suspended in the ethyl oleate with the aidof sonication, and analgesic activity was demonstrated using thephenylquinone writhing test.

EXAMPLE IV

An analgesic composition for oral administration is made using thefollowing ingredients:

N-vanillyl-9Z-octadecenamide: 100 g

Acetylsalicylic acid: 100 g

Ethyl oleate: 300 g

The composition is made by simple dissolution of the octadecenamide inthe ethyl oleate, followed by suspension of the finely dividedacetylsalicylic acid in the resulting solution by vigorous mechanicalblending under an inert atmosphere of argon or dry nitrogen. The creamysuspension is then loaded into soft gelatin capsules to deliver 325 mgacetylsalicylic acid and 325 mg N-vanillyl-9-octadecenamide per capsule.One such capsule is administered orally to a 60 kg human, producinganalgesia.

Substantially similar results are produced when the octadecenamide isreplaced, in whole or in part by capsaicin;N-vanillyl-9E-octadecenamide;N-[(4-acetoxy-3-methoxyphenyl)methyl]-9Z-octadecenamide;N-vanillyl-(Z,Z)-9,12-octadecadienamide;N-vanillyl-(E,E)-9,12-octadecadienamide;N-[(4-acetoxy-3-methoxyphenyl)methyl]-(E,E)-9,12-octadecadienamide;N-vanillyl-(E,E)-10,13-nonadecadienamide; N-vanillyl-9-octadecyanamide;9-methylene-N-octadecan-amide;9-methylene-N-[(4-acetoxy-3-methoryphenyl)-methyl]octadecanamide;4-acetoxy-3-methoxy-benzyl nonamide, or octyl3,4-dehydroxyphenylacetamide.

Substantially similar results are also obtained when the acetylsalicylicacid is replaced, in whole or in part, by the sodium, calcium, or lysinesalts of aspirin, ibuprofen, diflunisal, naproxen, mefenamic acid,fenoprofen, indomethacin, ketoprofen, suprofen, perprofen, carprofen, oran aspirin-phenacetin-caffeine combination (APC).

EXAMPLE V

A composition for oral administration is made with the followingcomponents:

    ______________________________________                                                                  Individual                                                           Bulk     Tablet                                              ______________________________________                                        N--vanillyl-9,12-octadecadienamide                                                               140 g      350    mg                                       Ibuprofen          35 g       90     mg                                       Starch             12 g       30     mg                                       Magnesium stearate  2 g       5      mg                                       Microcrystalline cellulose                                                                       40 g       100    mg                                       Colloidal silicon dioxide                                                                         1 g       2.5    mg                                       Povidone            5 g       12.5   mg                                       ______________________________________                                    

The above ingredients are admixed in bulk and formed into compressedtablets, using tabletting methods known in the art, each containing 590mg of the mixture. One such tablet is administered orally to a 60 kghuman, producing analgesia.

EXAMPLE VI

A composition for oral administration is made with the followingingredients:

N-vanillyl-9Z-octadecenamide: 225 g

Aspirin: 125 g

Phenacetin: 83 g

Caffeine: 17 g

Mannitol: 487 g

Acacia: 29.3 g

Starch: 48.1 g

Talc: 15 g

Calcium stearate: 2 g

The above ingredients are admixed in bulk and formed into tabletsweighing 100 mg each using tabletting methods known in the art. Two suchtablets are administered orally to a 70 kg human, producing analgesia.

EXAMPLE VII

A composition for transdermal topical delivery is made by admixing thefollowing components:

N-vanillyl-9,12,15[E,E,E]-octadecatrienamide: 4.0%

Ibuprofen: 1.0%

Myristyl alcohol: 1.0%

Propylene glycol: 94.0%

Approximately 4.0 ml of the lotion is applied to an 80 sq. cm. portionof the skin of a 60 kg human, producing analgesia.

Effectiveness in Providing Analgesia Phenylquinone Writhing Tests

The extent of analgesia obtained was determined using the phenylquinonewrithing test model. Groups of eight male mice weighing betweenapproximately 25 and 30 g were dosed orally by gavage with the analgesiccomposition to be tested. Identical groups of mixe were dosed withcontrol compositions. Three hours after this initial administration, themice were injected intraperitoneally with a 0.2% solution ofphenylbenzoquinone in aqueous ethanol. The ability of the analgesiccompositions tested to relieve the discomfort induced was measured bycounting the number of abdominal contractions, or "writhes", occurringin each mouse during a 10 minute period beginning 10 minutes afterinjection of the phenylbenzoquinone solution. The results are expressedas a percent of the "writhing" response observed in the vehicle controlgroup.

EXAMPLE VIII

An analgesic composition for oral administration was made using thefollowing ingredients:

N-vanillyl-9-octadecenamide: 120 mg

Aspirin: 60 mg

Methylcellulose: 30 mg

Saline: 6.0 ml

The composition was prepared by dissolving the methylcellulose in thesaline to yield a 0.5% solution, after which the solid aspirin andN-vanillyl-9-octadecenamide were added and uniformly suspended in thesolution by exposure to sonication.

Male mice weighing approximately 25 g were orally dosed with a volume ofthis suspension sufficient to deliver 200 mg/kg of the octadecenamideand 100 mg/kg of the aspirin. Identical groups of mice were dosed orallywith similarly prepared formulations which lacked either the aspirin,the octadecenamide, or both. The mouse "writhing" method for assessingpain response described above was used. The data, summarized in thefollowing table, were normalized based on the vehicle control taken as100.

    ______________________________________                                        Treatment             % Writhing Response                                     ______________________________________                                        Methylcellulose alone 100                                                     Octadecenamide (200 mg/kg)                                                                          54                                                      Aspirin (100 mg/kg)   78                                                      Aspirin (100 mg/kg) + octadecenamide                                                                10                                                      (200 mg/kg)                                                                   ______________________________________                                    

The response of the group given aspirin alone was not statisticallydistinguishable from that of the control group. The 90% inhibition ofthe writhing response resulting from the combination treatment (aspirinplus octadecenamide) is greater than that expected from the sum of theaspirin treatment (22% inhibition) and octadecenamide treatment (45%inhibition) when given separately.

EXAMPLE IX

An analgesic combination for oral administration was prepared in amanner similar to that decribed for Example I, the only difference beingthe ratio of aspirin to N-vanillyl-9-octadecenamide:

N-vanillyl-9-octadecenamide: 120 mg

Aspirin: 120 mg

Methylcellulose: 30 mg

Saline: 6.0 ml

A solution was prepared as described in Example I. The analgesicactivity of the combination was assessed in mice using the "writhing"method described above. The activity of the combination was contrastedwith those of similar formulations lacking the aspiring component, theoctadecenamide component or both:

    ______________________________________                                        Treatment             % Writhing Response                                     ______________________________________                                        Methylcellulose alone 100                                                     Aspirin (200 mg/kg)   15                                                      Octadecenamide (200 mg/kg)                                                                          33                                                      Aspirin (200 mg/kg) + octadecenamide                                                                1.5                                                     (200 mg/kg)                                                                   ______________________________________                                    

The analgesic efficacy obtained from the combination is significantlygreater than that from either component alone.

EXAMPLE X

An analgesic composition for oral administration was made using thefollowing ingredients:

N-vanillyl-9-octadecenamide: 120 mg

Ibuprofen: 30 mg

Methylcellulose: 30 mg

Saline: 6.0 ml

The methylcellulose suspending agent was dissolved in the saline toyield a 0.5% solution, to which the two drugs were added. A homogeneoussuspension was achieved by the aid of sonication. The analgesic efficacyof this formulation was evaluated by dosing the mice by gavage with asufficient dosage to provide 250 mg/kg of the mixture. The analgesicstrength of the treatment was assessed using the "writhing" methoddescribed above. The efficacy of the combination was compared with thatof similar formulations lacking the octadecenamide, the ibuprofen, orboth.

    ______________________________________                                        Treatment             % Writhing Response                                     ______________________________________                                        Methylcellulose alone 100                                                     Ibuprofen (50 mg/kg)  114                                                     Octadecenamide (200 mg/kg)                                                                           48                                                     Octadecenamide (200 mg/kg) + ibuprofen                                                               2                                                      (50 mg/kg)                                                                    ______________________________________                                    

In this case, the addition of an ineffective dose of ibuprofen to amoderately effective dose of octadecenamide resulted in a greatlypotentiated analgesic effect.

EXAMPLE XI

An analgesic composition for oral administration was made using thefollowing ingredients:

N-vanillyl-9-octadecenamide: 120 mg

Ibuprofen: 30 mg

Ethyl oleate: 6.0 ml

The two analgesics were suspended in ethyl oleate with the aid ofsonication, and evaluated for analgesic efficacy exactly as described inExample X.

    ______________________________________                                        Treatment             % Writhing Response                                     ______________________________________                                        Ethyl oleate alone    100                                                     Octadecenamide (200 mg/kg)                                                                           36                                                     Ibuprofen (50 mg/kg)  154                                                     Octadecenamide (200 mg/kg) + ibuprofen                                                               5                                                      (50 mg/kg)                                                                    ______________________________________                                    

Although the response of the group receiving 50 mg/kg of ibuprofen alonedid not vary significantly from that of the control group, the additionof this sub-effective amount of ibuprofen to the octadecenamide greatlypotentiated its analgesic effect. Further, the combination of ibuprofenwith the octadecenamide can provide anti-inflammatory/anti-arthritisefficacy lacking in N-vanillyl-9-octadecenamide and related capsaicinanalogs.

EXAMPLE XII

An analgesic composition for oral administration was made using thefollowing ingredients:

N-vanillyl-9Z-octadecenamide: 120 mg

3-(2',4'-diflurophenyl)-salicylic acid: (diflunisal): 60 mg

Ethyl oleate: 6.0 ml

The two analgesics were suspended in ethyl oleate with the aid ofsonication and were evaluated for analgesic efficacy as described inExample X.

    ______________________________________                                        TREATMENT        % WRITHING RESPONSE                                          ______________________________________                                        Ethyl oleate alone                                                                             100                                                          Diflunisal (100 mg/kg)                                                                         121                                                          Octadecenamide (200 mg/kg)                                                                      50                                                          Diflunisal (100 mg/kg) +                                                                        15                                                          Octadecenamide (200 mg/kg)                                                    ______________________________________                                    

In this case, the addition of an ineffective dose of diflunisal to amoderately effective dose of octadecenamide resulted in a greatlypotentiated analgesic effect. Additionally, diflunisal providesanti-inflammatory activity not possessed by the octadecenamide alone.

EXAMPLE XIII

An analgesic composition for oral administration was made using thefollowing ingredients:

N-vanillyl-9Z-octadecenamide: 75 mg

Acetaminophen: 75 mg

Ethyl oleate/benzyl alcohol (98:2 vol/vol): 5 ml

The two analgesics were suspended in the ethyl oleate solution with theaid of sonication and were evaluated as in Example X.

    ______________________________________                                        TREATMENT         % WRITHING RESPONSE                                         ______________________________________                                        Ethyl oleate solution alone                                                                     100                                                         Acetaminophen (150 mg/kg)                                                                       127                                                         Octadecenamide (150 mg/kg)                                                                       57                                                         Acetaminaphen (150 mg/kg) +                                                                      17                                                         octadecenamide (150 mg/kg)                                                    ______________________________________                                    

In this case, the addition of an ineffective dose of acetaminophen to amarginally effective dose of octadecenamide resulted in a greatlypotentiated analgesic effect.

EXAMPLE XIV

In order to determine the preferred capsaicinoid: non-steroidal ratios,an analgesic combination for oral administration was made using thefollowing ingredients:

1:1 Octadecenamide:aspirin Combination

N-vanillyl-9Z-octadecenamide: 75 mg

Aspirin: 75 mg

Ethyl oleate: 10 ml

1:2 Octadecenamide:aspirin Combination

N-vanillyl-9Z-octadecenamide: 50 mg

Aspirin: 100 mg

Ethyl oleate: 10 ml

1:5 Octadecenamide:aspirin Combination

N-vanillyl-9Z-octadecenamide: 25 mg

Aspirin: 125 mg

Ethyl oleate: 10 ml

The two analgesics were suspended in ethyl oleate with the aid ofsonication and were evaluated for analgesic efficacy as described inExample X.

    ______________________________________                                                              % WRITHING                                              TREATMENT             RESPONSE                                                ______________________________________                                        Ethyl oleate alone    100                                                     150 mg/kg aspirin     92                                                      150 mg/kg Octadecenamide                                                                            43                                                      150 mg/kg Octadecenamide:Aspirin (1:1)                                                              48                                                      150 mg/kg Octadecenamide:Aspirin (1:2)                                                              28                                                      150 mg/kg Octadeceaamide:Aspirin (1:5)                                                              77                                                      ______________________________________                                    

The responses of the ethyl oleate control group, the 1:5 combinationgroup (25 mg/kg octadecenamide+125 mg/kg aspirin) and the groupreceiving 150 mg/kg aspirin were not significantly different. The groupsreceiving the octadecenamide alone and the 1:1 combination (75 mg/kgaspirin+75 mg/kg octadecenamide) displayed a moderate analgesic effect.The group receiving the 1:2 combination (50 mg/kg octadecenamide+100mg/kg aspirin) displayed an analgesic effect unexpectedly superior tothat of any of the other groups.

Since the aspirin component of this combination provides ananti-inflammatory benefit not possessed by the octadecenamide or theother capsaidin analogs, and the octadecenamide provides greateranalgesia than is obtainable using aspirin alone without many of thelimitative side effects of aspirin, including gastrointestinal effects,the combination clearly provides benefits not attainable using eithercompound alone.

EXAMPLE XV

In order to determine the preferred dosages of thecapsaicinoid/non-steroidal combination in the rat, a 2:1octadecenamide:ibuprofen analgesic composition for oral administrationwas made using the following ingredients:

N-vanillyl-9Z-octadeceanmide: 100 mg

Ibuprofen: 50 mg

Ethyl oleate/benzyl alcohol (98.2 vol/vol): 5 ml

The two analgesics were suspended in the ethyl oleate solution with theaid of sonication, and varying dosages of the combination, as well asthe individual components, were evaluated for analgesic efficacy asdescribed in Example X.

    ______________________________________                                        TREATMENT         % WRITHING RESPONSE                                         ______________________________________                                        Ethyl oleate solution alone                                                                     100                                                          50 mg/kg ibuprofen                                                                             150                                                         100 mg/kg octadecenamide                                                                        83                                                          400 mg/kg octadecenamide                                                                        21                                                           75 mg/,kg 2:1 octadecenamide:                                                                  40                                                          ibuprofen combination                                                         150 mg/kg 2:1 octadecenamide:                                                                   6                                                           300 mg/kg 2:1 octadecenamide:                                                                   0.5                                                         ibuprofen combination                                                         ______________________________________                                    

All three dosage levels of the combination produced a significantanalgesic effect, although the 75 mg/kg dosage produced less analgesiathan the other two dosages. Preferred dosage levels will depend on theseverity of the pain to be treated, the relative severity of adverseside effects, and other factors within the judgment of the physician.

Although neither 50 mg/kg ibuprofen nor 100 mg/kg octadecenamideprovided significant analgesia by themselves, the 150 mg/kg combination(100 mg/kg octadecenamide+50 mg/kg ibuprofen) demonstrated an extremelystrong analgesic effect. Furthermore, only 150 mg/kg of the 2:1combination produced a greater analgesic effect than 400 mg/kg ofoctadecenamide alone, and only 75 mg/kg of the 2:1 combination(sub-effective amounts of both components) produced a greater analgesiceffect than 100 mg/kg of octadecenamide alone. These results indicate asynergistic increase in analgesia when the two analgesics are combined.

What is claimed is:
 1. An analgesic composition comprising a safe andeffective amount of:(a) a capsaicinoid analgesic compound of the generalformula: ##STR8## wherein R₁ is selected from the group consisting of OHand OCH₃, X is selected from the group consisting of ##STR9## and R is aC₁₆ -C₂₁ cis-mono-unsaturated alkenyl; (b) a nonsteroidal analgesicselected from the group consisting of salicylates, salicylate-likeanalgesic-antipyretics, and the pharmaceutically acceptable saltsthereof; and (c) a pharmaceutically-acceptable carrier; wherein theweight ratio of (a):(b) is from about 20:1 to about 1:20.
 2. Acomposition according to claim 1, wherein the weight ratio of (a):(b) isfrom about 10:1 to about 1:10.
 3. A composition according to claim 2,wherein the non-steroidal is selected from the group consisting ofsalicylates and their pharmaceutically-acceptable salts.
 4. Acomposition according to claim 3, wherein the non-steroidal isacetylsalicylic acid.
 5. A composition according to claim 4, wherein theweight ratio of capsaicinoid to acetylsalicylic acid is from about 3:1to about 1:3.
 6. A composition according to claim 5 wherein thecapsaicinoid is N-vanillyl-9-octadecenamide.
 7. A composition accordingto claim 6, wherein the weight ratio of N-vanillyl-9-octadecenamide toacetylsalicylic acid is about 2:1.
 8. A composition according to claim3, wherein the non-steroidal is diflunisal.
 9. A composition accordingto claim 8, wherein the weight ratio of capsaicinoid to diflunisal isfrom about 3:1 to about 1:3.
 10. A composition according to claim 9wherein the capsaicinoid is N-vanillyl-9-octadecenamide.
 11. Acomposition according to claim 2, wherein the non-steroidal is selectedfrom the group consisting of salicylate-like analgesic-antipyretics andtheir pharmaceutically-acceptable salts.
 12. A composition according toclaim 2, wherein the non-steroidal is acetaminophen.
 13. A compositionaccording to claim 12 wherein the weight ratio of capsaicinoid toacetaminophen is from about 2:1 to about 1:2.
 14. A method for providinganalgesia in humans and lower animals which comprises administeringconcurrently to a human and lower animal in need of such treatment asafe and effective amount of:(a) a capsaicinoid analgesic compound ofthe general formula: ##STR10## wherein R₁ is selected from the groupconsisting of OH and OCH₃, X is selected from the group consisting of##STR11## and R is a C₁₆ -C₂₁ cis-mono-unsaturated alkenyl; (b) anonsteroidal analgesic selected from the group consisting ofsalicylates, salicylate-like analgesic-antipyretics, and thepharmaceutically acceptable salts thereof; and wherein the weight ratioof (a):(b) is from about 20:1 to about 1:20.
 15. A method according toclaim 14, wherein the capsaicinoid is N-vanillyl-9-octadecenamide, thenon-steroidal is acetylsalicylic acid, and the weight ratio ofN-vanillyl-9-octadecenamide to acetylsalicylic acid is from about 3:1 toabout 1:3.
 16. A method according to claim 14, wherein the capsaicinoidis N-vanillyl-9-octadecenamide, the non-steroidal is difluinsal, and theweight ratio of N-vanillyl-9-octadecamide to diflunisal is from about3:1 to about 1:3.
 17. A method according to claim 14, wherein thecapsaicinoid is N-vanillyl-9-octadecenamide, the non-steroidal isacetaminophen, and the weight ratio of N-vanillyl-9-octadecenamide toacetaminaphen is from about 3:1 to about 1:3.